Summary of Work: We have used the patch clamp technique to study the regulation of potassium channel activity by reversible protein phosphorylation in two mammalian cell systems at the molecular level: calcium-activated potassium channels in rat pituitary tumor cells; and G protein activated potassium channels in guinea pig atrial myocytes. Channels encoded by the same genes also play essential roles in other electrically excitable tissues, where they prevent excitotoxicity, hypertension and stress. We have shown that both channels are stimulated by ser/thr directed protein phosphatases and inhibited by ser/thr directed kinases using hormones and pharmacological reagents on intact cells and purified enzymes on cell-free membrane patches. We have cloned the calcium-activated potassium channel gene from rat pituitary tumor cells and identified the structural basis for inhibition of the channels by protein kinases. We have found that estrogen alters potassium channel regulation by G proteins in the heart during maturation, and we have discovered a novel G protein-independent drug for opening the channels.